The overall goal of the proposed research program is to deliver antiviral therapeutics to macrophages that are infected with the single strand RNA viruses that cause hemorrhagic fevers and hepatitis. Our strategy is to use rehydrated, lyophilized (RL) platelets to deliver ribavirin to the macrophages of the reticuloendothelial system (RES) that are involved in the initial stage of viral infection, as well as macrophages at sites of vascular injury in the later acute-hemorrhagic phase of infection. Viruses of the Arenaviridea (e.g., Lassa fever virus), Filoviridae (e.g., Ebola and Marburg viruses), Bunyaviridae (e.g., Rift Valley virus) and Flaviviridae (e.g., Yellow fever virus) families cause viral-induced cellular damage to vascular tissues that result in hemorrhage. Similarly, hepatitis C virus (a Flaviviridae family member) propagation is frequently associated with bleedingintensive hepatic surgeries. Ribavirin, as a broad-spectrum antiviral RNA mutagen, holds promise for the treatment of these hemorrhage-associated viruses. However, adverse toxicities have limited the clinical use of this ribonucleoside as an antiviral chemotherapeutic. We seek to increase the therapeutic efficacy of ribavirin by using RL platelets to deliver the ribonucleoside. The intrinsic hemostatic function of RL platelets will thus concentrate the ribavirin in the microenvironment of the virus for increased chemotherapeutic efficacy; in RES and vascular wound site macrophages. Goal of the proposed research- Two specific research aims are proposed in this application. First, we will optimize the method for covalently attaching ribavirin to RL platelets in a form that is releasable in the low pH environment of the macrophage phagosome Secondly, the pharmokinetics of ribavirin delivery to elements of the RES and wound sites will be characterized. Overall Scope of the program. We anticipate that the proposed research will form the basis for studies (beyond the scope of this proposal) with non-human primates that will access the therapeutic utility of ribavirin loaded RL platelets as antiviral agents for the treatment of hemorrhagic fevers. The results of this research program hold promise for providing badly needed therapeutics for hemorrhagic fevers and hepatitis, and thus have biodefense as well as first and third worm public health implications.